Use of a polyphenol for the treatment of a cancerous or precancerous lesion of the skin

ABSTRACT

A method for treating cancerous or pre-cancerous lesions of the skin by administering a pharmaceutically effective amount of a polyphenol to a patient as well as to the production of a medicament thereto is described herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the U.S. National Stage of International ApplicationNo. PCT/EP2004/011300, filed Oct. 8, 2004, which claims benefit of U.S.Provisional Application No. 60/510,101, filed Oct. 9, 2003, herebyincorporated by reference.

The present invention refers to a method for treating cancerous orpre-cancerous lesions of the skin by administering a pharmaceuticallyeffective amount of a polyphenol to a patient as well as to theproduction of a medicament thereto.

Skin cancer is a disease in which malignant (cancer) cells are formed inthe tissues of the skin. The skin is the body's largest organ. Itprotects against heat, sunlight, injury, and infection, helps to controlthe body temperature and stores water, fat, and vitamin D. The skin hasseveral layers, but the two main layers are the epidermis (upper orouter layer) and the dermis (lower or inner layer). Skin cancer usuallystarts growing in the epidermis, which is made up of three kinds ofcells. The squamous cells are thin, flat cells that form the top layerof the epidermis. The basal cells are round cells below the squamouscells and melanocytes are found in the lower part of the epidermis.These cells produce melanin, the pigment that is responsible for thenatural color of the skin. When skin is exposed to the sun, melanocytesare induced to produce more pigment causing the skin to tan or darken.

Skin cancer can occur anywhere but it is most common in skin that hasbeen exposed to sunlight, such as the face, ears, neck, bald scalp,hands, shoulders, arms and/or the back. There are several types ofcancer that start in the skin. The most common types are basal cellcarcinoma and squamous cell carcinoma which are non melanoma skincancers. Actinic keratosis is a skin condition that sometimes developsinto squamous cell carcinoma.

Basal cell carcinoma or basalioma is the most common form of skin canceraffecting 800,000 Americans each year. In fact, it is the most common ofall cancers. One out of every three new cancers is a skin cancer and thevast majority are basal cell carcinomas often referred to by theabbreviation, BCC. These cancers arise in the basal cells which are atthe bottom of the epidermis (outer skin layer). Until recently, thosepeople which were most often affected, were older people, particularlymen who had worked outdoors. Although the number of new cases hasincreased sharply each year in the last few decades, the average age ofonset of the disease has steadily decreased. More women are getting BCCthan in the past. Nonetheless, men still outnumber them greatly. Chronicexposure to sunlight is the cause of almost all basal cell carcinomaswhich occur most frequently on exposed parts of the body. Rarely,however, tumors develop on non-exposed areas. In a few cases, contactwith arsenic, exposure to radiation and complications of burns, scars,vaccinations or even tattoos are contributing factors.

Squamous cell carcinoma (SCC), the second most common skin cancer afterbasal cell carcinoma, afflicts more than 200,000 Americans each year. Itarises from the epidermis and resembles the squamous cells that comprisemost of the upper layers of skin. Squamous cell cancers may occur on allareas of the body including the mucous membranes, but are most common inareas exposed to the sun. Although squamous cell carcinomas usuallyremain confined to the epidermis for some time, they eventuallypenetrate the underlying tissues if not treated. In a small percentageof cases they spread (metastasize) to distant tissues and organs whichcan be fatal for the person afflicted. Metastasing squamous cellcarcinomas most often arise on sites of chronic inflammatory skinconditions or on the mucous membranes or lips. Chronic exposure tosunlight causes most cases of squamous cell carcinoma because tumorsappear most frequently on sun-exposed parts of the body. The rim of theear and the lower lip are especially vulnerable to the development ofthese cancers. Squamous cell carcinomas may also occur where skin hassuffered certain kinds of injury such as burns, scars, long-standingsores, sites previously exposed to X-rays and/or certain chemicals suchas arsenic and petroleum by-products. In addition, chronic skininflammation or medical conditions that suppress the immune system overan extended period of time may encourage development of squamous cellcarcinoma. Occasionally, squamous cell carcinoma arises spontaneously onwhat appears to be normal, healthy or undamaged skin. Some researchersbelieve that a teridency to develop this cancer may be inherited.

Certain precursor conditions, some of which result from extensive sundamage, are sometimes associated with the later development of squamouscell carcinoma. They include actinic keratoses, actinic cheilitis,leukoplakia and Bowen's disease.

Actinic keratosis (AK), also known as a solar keratosis, arises on theskin surface. AK appears as rough, scaly crusty and/or slightly raisedgrowths that range in color from brown to red and may be up to one inchin diameter. It appears most often in older people. The base may belight or dark, tan, pink, red or a combination of these or has the samecolor as the skin itself. The scale or crust is horny, dry and rough andis often recognized by touch rather than sight. Occasionally, it itchesor produces a pricking or tender sensation. It can also become inflamedand surrounded by redness. In rare instances, actinic keratoses can evenbleed. The skin abnormality or lesion develops slowly and generallyreaches a size from an eighth to a quarter of an inch. Early on, it maydisappear only to reappear later. Several Aks can often been seen at atime and are most likely to appear on the parts of the body most oftenexposed to sunshine. The growths may be flat and pink or raised andrough. AK can be the first step in the development of skin cancer. It isthus a precursor of cancer or a precancer. If treated early, almost allAKs can be eliminated without becoming skin cancers. But untreated,about two to five percent of these lesions may progress to squamous cellcarcinomas. In fact, some scientists now believe that AK is the earliestform of Squamous Cell Carcinoma (SCC). These cancers are usually notlife-threatening, provided they are detected and treated in the earlystages. However, if this is not done, they can grow large and invade thesurrounding tissues and, on rare occasions, metastasize or spread to theinternal organs.

Actinic cheilitis is another form of actinic keratosis which occurrs onthe lips and causes them to become dry, cracked, scaly and pale orwhite. It mainly affects the lower lip, which typically receives moresun exposure than the upper lip, and may evolve into a type of SCC thatcan spread rapidly to other parts of the body.

Chronic sun exposure is the cause of almost all AKs. Sun damage to theskin accumulates over time, so that even a brief exposure adds to thelifetime total. The likelihood of developing AK is highest in regionsnear the equator. However, regardless of climate, everyone is exposed tothe sun. About 80 percent of solar UV rays can pass through clouds.These rays can also bounce off sand, snow and other reflective surfacesgiving you extra exposure. AKs can also appear on skin that has beenfrequently exposed to artificial sources of UV light, such as tanningdevices. More rarely, they may be caused by extensive exposure to X-raysor specific industrial chemicals. Individuals whose immune systems areweakened as a result of cancer chemotherapy, AIDS or organtransplantation are also at higher risk. AK is the most common type ofprecancerous skin lesion. Older people are more likely than younger onesto develop these lesions because cumulative sun exposure increases withthe years. Some experts believe that the majority of people who live tothe age of 80 will have AK.

Leukoplakia, another precursor condition, are white patches on thetongue or inside of the mouth having the potential to develop intosquamous cell carcinoma.

Bowen's disease is generally considered to be a superficial squamouscell cancer that has not yet spread. It appears as a persistentred-brown, scaly patch which may resemble psoriasis or eczema. Ifuntreated, it may invade deeper structures.

The standard therapies used in pre-cancerous or cancerous lesions of theskin might not be applicable in all patients, e.g. surgery in patientswith severe concomitant diseases, or have severe side-effects and mayresult in skin breakdown, discoloration, irritation, damage tosurrounding normal skin, swelling and/or scars.

Consequently, the problem underlying the present invention resides inproviding an alternative therapy for pre-cancerous or cancerous lesionsof the skin for at least most of the group of patients.

Surprisingly, it has been found that the treatment of the skin with atleast one polyphenol, in particular with at least one catechin elicits apositive effect on pre-cancerous or cancerous lesions of the skin.

One subject-matter of the present invention is, therefore, a method fortreating a cancerous, including pre-cancerous, lesion of the skin byadministering a pharmaceutically effective amount of a polyphenol or amixture of polyphenols to a patient, in particular to a human.

In a preferred embodiment the lesion of the skin is a non-virallyinduced lesion, in particular a lesion not caused by a papilloma virus,preferably not a lesion selected from hyperplasia, Condyloma acuminata,warts, including without limitation common warts and/or plantar warts,and/or cervical intra-epithelial neoplasia.

According to the present invention, the term “non-virally inducedcancerous lesion” means a cancerous and/or pre-cancerous condition ofthe skin which is not caused or induced by viruses which can infect theskin, such as papilloma viruses, in particular human papilloma viruses,e.g. HPV 1, 2, 3, 4, 5, 6, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19-29,31, 32, 34, 36-38, 46-50 and/or 56-58, and/or herpes viruses, such asherpes simplex virus 1, herpes simplex virus 2, varicella zoster virusand/or human herpes virus, such as HHV 1, 2, 3, 4, 7 and/or 8. Examplesof diseases caused or induced by viruses are verrucae plantares,verrucae vulgares, verrucae planae juveniles, epidermodysplasiaverruciformis, Condylomata acuminata, Condylomata plana, bowenoidpapulosis, papillomas on the larynx and oral mucosa, focal epithelialhyperplasia, herpes labialis, Kaposi's sarcoma, varicella and shingles.

The term “pharmaceutically effective amount” means an amount of at leastone polyphenol which causes a positive effect on the lesion of the skinof the patient, e.g. causes a reduction or disappearance of the lesion,in particular with the aim to improve or cure the disease of thepatient. Pharmaceutically effective amounts are e.g. formulations,preferably ointments, containing about 2% (w/w) to about 50% (w/w),especially about 5% (w/w) to about 20% (w/w), in particular about 10%(w/w) to about 15% (w/w) and most preferred about 10% (w/w) or about 15%(w/w) of at least one polyphenol or of a mixture of several (different)polyphenols. These amounts can be applied once or several times, e.g. 3to 5 times a week for 6 to 12 weeks, until the positive effect on thelesion of the skin of the patient occurs.

The term “about” means according to the invention a general error rangeof +/−20%, especially +/−10%, in particular +/−5%.

Polyphenols are naturally accurring phenolic compounds, preferably with1, 2 or 3 aromatic rings, in particular with 2 aromatic rings, carryingat least two hydroxyl groups, such as catechols, flavons, flavonoidsand/or anthocyanidins, e.g. pelargonidin, cyanidin, delphinidin,paonidin, petunidin, malvidin and/or hirsutidin, whereas catechols arenaturally occurring polyphenols usually found in resins and/or lignins.Alternative names used in the literature for catechols are catechins,pyrocatechols or 1,2-dihydroxybenzenes.

The polyphenols, in particular the catechols employed in the presentinvention may be obtained either synthetically or from natural sources.The natural sources which may especially be mentioned are tea plants, inparticular green tea. In this context, the natural constituents may bepresent in differing concentrations depending on the species andvariety. In this connection, the polyphenols,in particular the catecholswhich are employed are preferably isolated or extracted from Camelliasinensis, Camellia asamica, Camellia bohea, Camellia chinensis and/orCamellia oleosa. All the components of tea plants, in particular theleaves, can be used for isolating or extracting the polyphenols, inparticular the catechols. The polyphenols, in particular the catecholswhich are employed are preferably isolated from a tea extract, inparticular from a green tea extract or easily extracted from a tea, inparticular from a green tea. Suitable methods for the isolation orextraction of polyphenols, in particular catechols are described e.g. inU.S. Pat. Nos. 4,613,672, 4,673,530, 4,913,909, 6,096,359 or 4,248,789.

Generally, the polyphenols have the formula (I)

in which

-   R₁, R₂ and R₆ are independently from each other —H or —OH,-   R₃ is —H or ═O,-   R₄ is independently from each other —H, —OH or a group of the    formula (III)

-   R₅ and R₇ are independently from each other —H, —OH or —OCH₃, and —    optionally represents a bond,    and the catechols have the formula (II)

in which

-   R₈ is —H or —OH, and-   R₉ is —H or a group of the formula (III)

Examples of polyphenols are:Polyphenol derivatives of flavan with the formula (IV):

Polyphenol derivatives of flavan-3-ol with the formula (V):

Polyphenol derivatives of flavanon with the formula (VI):

Polyphenol derivatives of flavon with the formula (VII):

Polyphenol derivatives of flavonol with the formula (VIII):

Polyphenol derivatives of chalcon with the formula (IX):

and anthocyanidins with the formula (X):

with R₅ and R₇ are independently from each other —H, —OH or —OCH₃, ase.g. in pelargonidin, cyanidin, delphinidin, paonidin, petunidin,malvidin or hirsutidin.

Preferably, the catechol is selected from catechol, catechol gallate,epicatechol, epicatechol gallate, epigallocatechol, epigallocatecholgallate, gallocatechol and/or gallocatechol gallate and in particularfrom (+)-catechol, (−)-catechol, (+)-catechol gallate, (−)-catecholgallate, (+)-epicatechol, (−)-epicatechol, (+)-epicatechol gallate,(−)-epicatechol gallate, (+)-epigallocatechol, (−)-epigallocatechol,(+)-epigallocatechol gallate, (−)-epigallocatechol gallate,(+)-gallocatechol, (−)-gallocatechol, (+)-gallocatechol gallate and(−)-gallocatechol gallate.

The structural formula of the most preferred catechols are:

For (−)-epigallocatechol gallate (−)-EGCG:

For (−)-epigallocatechol (−)-EGC:

For (−)-epicatechol gallate (−)-ECG:

For (—)-epicatechol (—)-EC:

For (+)-epicatechol (+)-EC:

For (+)-catechol (+)-C:

For (−) catechol (−)-C:

For (−)-gallocatechol gallate (−)-GCG:

For (−)-catechol gallate (−)-CG:

For (+)-gallocatechol (+)-GC:

For (−)-gallocatechol (−)-GC:

In another particularly preferred embodiment of the present inventionthe polyphenols, in particular the catechols, are present in the form ofa mixture of polyphenols, in particular catechols, especially containingcatechol, catechol gallate, epicatechol, epicatechol gallate,epigallocatechol, epigallocatechol gallate, gallocatechol and/orgallocatechol gallate, preferably in the stereochemistry as definedabove. The preferred catechols are in particular the gallates ofcatechol, epicatechol, epigallocatechol or of gallocatechol, as they aregenerally more active as the catechols. In particular, the presentinvention is directed to mixtures of the particular gallates containingmore than about 40% (w/w), preferably more than about 50% (w/w),especially more than about 60% (w/w) and in particular more than 65%(w/w) of the particular gallates. These gallates may be (−) or (+)stereoisomers wherein the (−) stereoisomers are preferred.

Preferred catechols employed in the present invention are(−)-epicatechol, (−)-epicatechol gallate, (−)-epigallocatechol,(−)-epigallocatechol gallate, (+)-gallocatechol and/or (−)-gaflocatecholgallate, in particular in form of a mixture containing about 2-20% (w/w)epicatechol, about 2-20% (w/w), epicatechol gallate, about 1-25% (w/w)epigallocatechol, about 40-75% (w/w) epigallocatechol gallate, about0.05-5% (w/w) gallocatechol and/or about 0.5-20% (w/w) gallocatecholgallate, especially a mixture containing about 10.8% (w/w) ofepicatechol, about 6.5% (w/w) of epicatechol gallate, about 9.2% (w/w)of epigallocatechol, about 54.8% (w/w) of epigallocatechol gallateand/or about 4.0% (w/w) of gallocatechol gallate, all of them preferablyin the stereochemistry as defined above, in particular in form of amixture containing about 10.8% (w/w) of (−)-epicatechol, about 6.5%(w/w) of (−)-epicatechol gallate, about 9.2% (w/w) of(−)-epigallocatechol, about 54.8% (w/w) of (−)-epigallocatechol gallateand/or about 4.0% (w/w) of (−)-gallocatechol gallate.

Alternatively, the mixture of catechols contains about 2-12% (w/w),preferably about 5-8% (w/w) epicatechol, about 4-15% (w/w), preferablyabout 5-7% (w/w), in particular about 5-6% (w/w) epicatechol gallate,about 1-8% (w/w), preferably about 2-3% (w/w), in particular about 6-8%(w/w) epigallocatechol, about 60-68% (w/w), preferably about 61-65%(w/w) epigallocatechol gallate, about 0.05-1% (w/w) gallocatechol andabout 1-7% (w/w), preferably about 2-4% (w/w) gallocatechol gallate.

Consequently, the catechols can be used both individually and in theform of mixtures having different compositions as specified above. Forexample, a composition known under the tradename Polyphenon® 100 iscomposed of about 5.9% (w/w) of (−)-epicatechol, about 12.6% (w/w) of(−)-epicatechol gallate, about 17.6% (w/w) of (−)-epigallocatechol,about 53.9% (w/w) of (−)-epigallocatechol gallate and/or about 1.4%(w/w) of (−)-gallocatechol. As another example, a composition knownunder the tradename Polyphenon® E is composed of about 10.8% (w/w) of(−)-epicatechol, about 6.5% (w/w) of (−)-epicatechol gallate, about 9.2%(w/w) of (−)-epigallocatechol, about 54.8% (w/w) of (−)-epigallocatecholgallate and/or about 4.0% (w/w) of (−)-gallocatechol gallate.

The familiar methods of pharmaceutical technology are used, in acustomary manner, for preparing pharmceuticals which comprise one ormore compounds according to the present invention and/or for using thesepharmaceuticals in the application according to the invention. For this,the active compounds are worked up, together with one or more suitable,pharmaceutically acceptable additives, if necessary, into the medicinalforms which are suitable for the different indications and sites ofadministration. In this context, the pharmaceuticals can be preparedsuch that the rate of release in each case desired, for example a rapidaccumulation and/or a delayed-release or depot effect, is achieved.

Consequently, another embodiment of the present invention is directed tothe use of a pharmaceutical effective amount of a polyphenol, inparticular a catechol or a mixture of (different) polyphenols, inparticular catechols, as specified above, for the production of amedicament for the treatment of cancerous, including pre-cancerous,lesions of the skin, preferably a non-virally induced lesion, inparticular a lesion not caused by a papilloma virus, preferably not alesion selected from hyperplasia, Condyloma acuminata, warts, includingwithout limitation common warts and/or plantar warts, and/or cervicalintra-epithelial neoplasia, as explained therein, preferably for thetopical administration of the polyphenol, in particular catechol, orpolyphenol, in particular catechol mixture.

Examples of suitable additives are sodium alginate, as a gelatinizingagent for preparing a suitable base, or cellulose derivatives, such asguar or xanthan gum, inorganic gelatinizing agents, such as aluminumhydroxide or bentonites (what are termed thixotropic gel-formers),polyacrylic acid derivatives, such as Carbopol®, polyvinylpyrrolidone,microcrystalline cellulose and carboxymethylcellulose. Amphiphilic lowmolecular weight and higher molecular weight compounds, and alsophospholipids, are also suitable. The gels can be present either aswater-based hydrogels or as hydrophobic organogels, for example based onmixtures of low and high molecular weight paraffin hydrocarbons andvaseline. The hydrophilic organogels can be prepared, for example, onthe basis of high molecular weight polyethylene glycols. Thesegelatinous forms are washable. However, the organogels which arepreferred are the hydrophobic organogels. Particular preference is givento hydrophobic additives, such as petroleum jelly, wax, oleyl alcohol,propylene glycol monostearate and/or propylene glycolmonopalmitostearate, in particular isopropyl myristate. It is, ofcourse, likewise possible to add skin-sedating and/orinflammation-inhibiting additives which are known to the skilled person,such as synthetically prepared active compounds and/or extracts and/oractive compounds from medicinal plants, in particular bisobolol andpanthenol. It is furthermore also possible to add dyes, for exampleyellow and/or red iron oxide and/or titanium dioxide for the purpose ofmatching as regards color.

Generally, the polyphenol, in particular the catechol or mixture ofpolyphenols, in particular catechols, is contained in a carrier, e.g. inthe form of an emulsion, a gel, a cream or an ointment.

Customary emulsions, gels, creams and ointments of the mixed-phase oramphiphilic emulsion systems (oil/water-water/oil mixed phase), and alsoliposomes and transfersomes or plasters, preferably ointments andcreams, particularly preferably an ointment, may be mentioned forconventional application to the skin. The catechol is preferably appliedlocally in the region in which there is a cancerous or pre-cancerousskin lesion.

Emulsifiers which can be employed are anionic, cationic or neutralsurfactants, for example alkali metal soaps, metal soaps, amine soaps,sulphurated and sulphonated compounds, invert soaps, higher fattyalcohols, partial fatty acid esters of sorbitan and polyoxyethylenesorbitan, e.g. lanette types, wool wax, lanolin or other syntheticproducts for preparing the oil/water and/or water/oil emulsions.

It is possible to use vaseline, natural or synthetic waxes, fatty acids,fatty alcohols, fatty acid esters, for example as monoglycerides,diglycerides or triglycerides, paraffin oil or vegetable oils,hydrogenated castor oil or coconut oil, hog fat, synthetic fats, forexample based on, caprylic acid, capric acid, lauric acid or stearicacid, such as Softisan®, or triglyceride mixtures, such as Miglyol®, canbe used as lipids, in the form of fatty and/or oleaginous and/or waxycomponents for preparing the ointments, creams or emulsions.

It is possible to use, for example, osmotically active acids andalkaline solutions, for example hydrochloric acid, citric acid, sodiumhydroxide solution, potassium hydroxide solution, sodium hydrogencarbonate, and, in addition, buffer systems, such as citrate, phosphate,tris buffer or triethanolamine, for adjusting the pH. It is possible toadd preservatives as well, such as methyl benzoate or propyl benzoate(parabens) or sorbic acid, for increasing the stability.

Pastes, powders and solutions may be mentioned as additional forms whichcan be applied topically. As consistency-imparting bases, the pastesfrequently contain hydrophobic and hydrophilic auxiliary substances,preferably, however, hydrophobic auxiliary substances containing a veryhigh proportion of solids. In order to increase dispersity, and alsoflowability and slipperiness, and also to prevent agglomerates, thepowders or topically applicable powders can, for example, contain starchspecies, such as wheat or rice starch, flame-dispersed silicon dioxideor siliceous earth, which also serve as diluent.

The medicinal forms which are in each case suitable can be produced onthe basis of pharmaceutico-physical principles in conformity withformulation guidelines and methods known to a skilled person.

As a further example, the pharmaceutical employed in the presentinvention preferably comprises about 35% (w/w) of isopropyl myristate,about 15% (w/w) of at least one catechol, about 24.5% (w/w) of petroleumjelly, about 20% (w/w) of wax, about 5% (w/w) of propylene glycolmonostearate or propylene glycol monopalmitostearate and about 0.5%(w/w) of oleyl alcohol.

An alternative embodiment of the present invention is directed to acombination therapy.

Therefore, the present invention also encompasses a method for treatinga cancerous, including pre-cancerous, lesion of the skin, preferably anon-virally induced lesion, in particular a lesion not caused by apapilloma virus, preferably not a lesion selected from hyperplasia,Condyloma acuminata, warts, including without limitation common wartsand/or plantar warts, and/or cervical infra-epithelial neoplasia, asexplained therein, by administering a pharmaceutically effective amountof a catechol or a mixture of catechols, as specified above, incombination with a different anticancer treatment and the preparation ofa corresponding medicament. The administration of the differentanticancer agent can be simultaneous with, prior to or after theadministration of the polyphenol, in particular catechol or the mixtureof polyphenols, in particular catechols.

According to the present invention the term “different anticancertreatment” refers preferably to surgery, electrodessication, curettage,excision, Mohs micrographic surgery, radiation, proton therapy,chemotherapy, photodynamic therapy, cryosurgery, laser, immunotherapy,vaccine therapy and/or biologic therapy. Preferred chemotherapeutictreatments encompass the use of podophyllin, 5-fluorouracil, bleomycin,interferon or imiquimod, and mixtures thereof. A preferred radiotherapyis X-ray radiation and/or γ-radiation.

The skin lesions referred to in the present invention are preferablyskin cancer or cutaneous carcinoma, basal cell carcinoma, squarnous cellcarcinoma, actinic or solar keratosis, epithelioma or epithelial tumors,skin neoplasm, Bowen's disease, acanthoma, cancroid, cutaneous horn,hyperkeratosis, keratosis, molluscum contagiosum, lid tumors,xanthelasma, xanthoma, fibroma, verucca senilis, seborrheic keratosis,cheilocarcinoma, papillomatosis, penis carcinoma, radiodermatitis,sailor's skin, tar cancer, vaginal carcinoma, vulvar cancer,erythroplasia queyrat and/or carcinoma of the tongue. In particular, theskin lesions are actinic or solar keratosis and/or basal cell carcinoma.

Taken together, one of the most preferred embodiments of the presentinvention is the use of a pharmaceutical formulation containing amixture of different polyphenols as disclosed above in an amount ofabout 10% (w/w) to about 15% (w/w) in the pharmaceutical formulation forthe treatment of actinic keratosis, solar keratosis and/or basal cellcarcinoma. The mixture of different polyphenols contains in particularmore than 60% (w/w), especially more than 65% (w/w) gallates ofcatechol, epicatechol, epigallocatechol or of gallocatechol. Preferredmixtures of different polyphenols are Polyphenon® 100 or Polyphenon® Eas specified above. Finally, a preferred pharmaceutical formulationcomprises about 35% (w/w) of isopropyl myristate, about 15% (w/w) of atleast a mixture of different polyphenols as specified in this paragraph,in particular Polyphenone® 100 or Polyphenon® E, about 24.5% (w/w) ofpetroleum jelly, about 20% (w/w) of wax, about 5% (w/w) of propyleneglycol monostearate or propylene glycol monopalmitostearate and about0.5% (w/w) of oleyl alcohol which can be used in the treatment ofactinic keratosis, solar keratosis and/or basal cell carcinoma.

The following examples are intended to clarify the invention withoutrestricting it. Skilled persons can modify the invention appropriately,within the bounds of customary ability, without departing from theprotective scope.

EXAMPLE 1

Patient: 65 years old, male with actinic keratoses known since 10 years;

The patient was treated with Polyphenon® E (15% ointment containing 35%(w/w) isopropyl myristate, 15% (w/w) catechol extract, 24.5% (w/w)petroleum jelly, 20% (w/w) wax, 5% (w/w) propylene glycol monostearateand 0.5% (w/w) oleyl alcohol):

Treated area: about 5 cm² on the forehead

Treatment schedule: 5 times a week (each with 10 hours)

Treatment period: 6 weeks

Treatment progression:

-   -   after about 13 days of treatment skin irritation of the treated        area (more precisely treated areas afflicted by actinic        keratoses) occurred    -   also an up-regulation of subclinical lesions occurred    -   skin irritation ameliorated during further treatment    -   after 12 weeks of treatment actinic keratoses have disappeared        completely

EXAMPLE 2

Patient: 73 years old, male with actinic keratoses known since about 15years, multiply pre-treated;

The patient was treated with Polyphenon® E (15% ointment containing 35%(w/w) isopropyl myristate, 15% (w/w) catechol extract, 24.5% (w/w)petroleum jelly, 20% (w/w) wax, 5% (w/w) propylene glycol monostearateand 0.5% (w/w) oleyl alcohol):

Treated area: about 5 cm² on the head

Treatment schedule: 3 times a week

Treatment period: 12 weeks

Treatment progression:

-   -   after 3.5 weeks of treatment skin irritation of the treated area        afflicted by actinic keratoses occurred (but less intense than        that of the patient of Example 1)    -   after 12 weeks of treatment only single actinic keratoses have        been left and after 16 weeks of treatment actinic keratoses have        disappeared completely.

1. A method for treating a keratosis lesion of the skin of a patient,said method comprising topically administering to the keratosis lesion apharmaceutically effective amount of a polyphenol composition comprising(i) a mixture of polyphenols and (ii) a carrier, wherein the compositioncomprises from about 5% (w/w) to about 20% (w/w) of the mixture ofpolyphenols, wherein the mixture of polyphenols contains epicatechol,epicatechol gallate, epigallocatechol, epigallocatechol gallate, andgallocatechol gallate.
 2. The method according to claim 1, wherein thepatient is a human.
 3. The method according to claim 1, wherein themixture of polyphenols is isolated from a tea or a tea extract.
 4. Themethod according to claim 3, wherein the tea is a green tea.
 5. Themethod according to claim 1, wherein the mixture of polyphenols contains(−) -epicatechol, (−)-epicatechol gallate, (−)-epigallocatechol,(−)-epigallocatechol gallate, and (−)-gallocatechol gallate.
 6. Themethod according to claim 1, wherein the mixture of polyphenols containsabout 2-20% (w/w) epicatechol, about 2-20% (w/w) epicatechol gallate,about 1-25% (w/w) epigallocatechol, about 40-75% (w/w) epigallocatecholgallate, and about 0.5-20% (w/w) gallocatechol gallate.
 7. The methodaccording to claim 6, wherein the mixture of polyphenols contains about10.8% (w/w) of (−)-epicatechol, about 6.5% (w/w) of (−)-epicatecholgallate, about 9.2% (w/w) of (−)-epigallocatechol, about 54.8% (w/w) of(−)-epigallocatechol gallate and about 4.0% (w/w) of (−)-gallocatecholgallate.
 8. The method according to claim 1, wherein the mixture ofpolyphenols is combined with an additive.
 9. The method according toclaim 8, wherein the additive is selected from the group consisting ofpetroleum jelly, wax, oleyl alcohol, propylene glycol monostearate,propylene glycol monopalmitostearate and isopropyl myristate.
 10. Themethod according to claim 1, wherein the mixture of polyphenols iscontained in a carrier selected from the group consisting of anemulsion, a gel, a cream and an ointment.
 11. The method according toclaim 1, wherein the method for treating said lesions is combined with adifferent anticancer treatment.
 12. The method according to claim 11,wherein the different anticancer treatment is selected from the groupconsisting of surgery, electrodessication, curettage, excision, Mohsmicrographic surgery, radiation, proton therapy, chemotherapy,photodynamic therapy, cryosurgery, laser, immunotherapy, vaccine therapyand biologic therapy.
 13. The method according to claim 1, wherein thekeratosis lesion of the skin is selected from the group consisting ofactinic keratosis, solar keratosis, hyperkeratosis, and seborrheickeratosis.
 14. The method according to claim 13, wherein the lesion ofthe skin is actinic keratosis.
 15. The method according to claim 1,wherein the composition comprises about 15% (w/w) mixture ofpolyphenols.
 16. A method for treating an actinic keratosis of the skinof a human, said method comprising topically administering to theactinic keratosis lesion a pharmaceutically effective amount of apolyphenol composition comprising (i) a mixture of polyphenols and (ii)a carrier, wherein the composition comprises about 15% (w/w) mixture ofpolyphenols, wherein the mixture of polyphenols contains about 10.8%(w/w) of (−)-epicatechol, about 6.5% (w/w) of (−)-epicatechol gallate,about 9.2% (w/w) of (−) -epigallocatechol, about 54.8% (w/w) of(−)-epigallocatechol gallate and about 4.0% (w/w) of (−)-gallocatecholgallate.